The invention relates to the use of at least one substituted 1-amino-5-phenylpentane-3-ol and/or 1-amino-6-phenylhexane-3-ol compound and/or one of the enantiomers thereof and/or one of the diastereomers thereof and/or one of the corresponding physiologically tolerable salts thereof in the manufacture of a medicament with an N-methyl-D-aspartate (NMDA) antagonistic effect.
Knowledge of the physiological significance of ion channel selective substances has been gained through the development of the patch clamp technique. Of particular significance is the NMDA ion channel, through which a considerable proportion of synapse communications runs. The exchange of calcium ions between a neuronal cell and its environment is controlled by this ion channel. The effect of NMDA antagonists on the flow of calcium ions into the interior of the cell can be demonstrated using the patch clamp technique.
In an inactivated state, the NMDA ion channels are closed by single magnesium ions which are inside the channel but cannot pass therethrough owing to their size. In an activated state, the smaller calcium and sodium ions can pass through the channel. The (+)-MK801 binding site of the NMDA ion channel (ionotropic NMDA receptor) is also inside this membrane protein. Substances with an NMDA anatagonist effect, such as phencyclidine (PCP), ketamine or MK801 occupy this binding site (so-called xe2x80x9cchannel blockersxe2x80x9d) and thus close the NMDA ion channel in question.
NMDA ion channels play an important role in many physiological and pathophysiological processes, such as, for example, epilepsy, schizophrenia, neurodegenerative diseases, especially in Alzheimer""s disease, Huntington""s disease and Parkinson""s disease, cerebral ischaemia and infarction, psychoses caused by raised amino acid level, cerebral oedema, under-supply of the central nervous system, in particular with hypoxia and anoxia, AIDS dementia, encephalomyelitis, Tourette""s syndrome, perinatal asphyxia and tinnitus.
The aim of this invention was therefore to make medicaments available which exhibit an NMDA antagonist effect and are therefore suitable for the preventative treatment of cerebrovascular attacks (strokes) and/or the treatment of epilepsy and/or schizophrenia and/or neurodegenerative diseases, in particular Alzheimer""s disease, Huntington""s disease or Parkinson""s disease and/or cerebral ischaemia and/or cerebral infarction and/or psychoses caused by raised amino acid level and/or cerebral oedema and/or under-supply of the central nervous system, in particular hypoxia and/or anoxia and/or AIDS dementia and/or encephalomyelitis and/or Tourette""s syndrome and/or perinatal asphyxia and/or tinnitus.
Surprisingly, it was found that substituted 1-amino-5-phenylpentane-3-ol and 1-amino-6-phenylhexane-3-ol compounds of general formula I below and the enantiomers, diastereomers and physiologically tolerable salts thereof exhibit a marked NMDA antagonistic effect and therefore are highly suitable for influencing the above mentioned physiological and pathophysiological processes.
The object of this invention is the use of at least one substituted 1-amino-5-phenylpentane-3-ol and/or 1-amino-6-phenylhexane-3-ol compound of general formula I, 
where n=1 or 2,
group A represents an optionally substituted aryl or heteroaryl group,
groups R1 and R2, the same or different, stand for a C1-6 alkyl group, preferably a C1-3 alkyl group, or groups R1 and R2 together form a (CH2)2-6 chain, which may also be phenyl substituted or may be attached to a phenyl ring to form a bicyclic system in which the cyclic aliphatic moiety and the phenyl ring share two carbon atoms.
groups R3 and R4, the same or different, stand for a C1-6 alkyl group, preferably a C1-3 alkyl group, preferable a C1-3 alkyl group, an optionally substituted aryl group or optionally substituted aryl group which is bound via a C1-3 alkylene group, or groups R3 and R4 together represent (CH2)3-6 or CH2CH2OCH2CH2,
groups R5, R6 and R7, the same or different, represent H, F, Cl, Br, I, CF3, OR8, SO2CH3, SO2CF3, phenyl, CN, NO2 or a C1-6 alkyl group, preferably a C1-3 alkyl group,
group R8 stands for H, a C1-6 alkyl group, preferably a C1-3 alkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group or for a optionally substituted aryl or heteroaryl group which is bound via a C1-3 alkylene group,
and/or one of the enantiomers thereof and/or one of the diastereomers thereof and/or a corresponding physiologically tolerable salt for the manufacture of a medicament with an NMDA antagonistic effect.
Physiologically tolerable salts of the compounds of general formula I and/or enantiomers thereof and/or diastereomers thereof may be hydrochloride, hydrobromide, sulphate, sulphonate, phosphate, tartrate, embonate, formate, acetate, propionate, benzoate, oxalate, succinate, citrate, glutamate, fumarate, aspartate, glutarate, stearate, butyrate, malonate, lactate, mesylate or a mixture of at least two of these salts.
Alkyl groups means branched, unbranched and cyclic hydrocarbon groups, which can also be substituted at least simply, preferably with a halogen group and/or a hydroxyl group, particularly preferably with fluorine and/or a hydroxyl group. If these alkyl groups contain more than one substituent, then these substituent may be the same or different. The alkyl groups are preferably methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 1,2-diemethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, cyclopropyl, cyclopropylmethyl, 2-methylcyclopropyl, cyclopentyl, cyclohexyl, CHF2, CF3 or CH2OH.
An aryl group also means at least a phenyl or naphthyl group substituted simply with an OR8, halogen, preferably F and/or Cl, CN, NO2, C1-6 alkyl or phenyl group, whereby the R8 group has the meaning according to general formula I. The phenyl groups can also be condensed with further rings.
A heteroaryl group also means 5- or 6-member, unsaturated, heterocyclic compounds, optionally containing fused aryl groups, which contain at least one heteroatom, preferably nitrogen, oxygen or sulphur, particularly preferably nitrogen or oxygen and which optionally also can be substituted at least simply with an OR8, halogen, preferably F and/or Cl, CN, NO2, C1-6 alkyl or phenyl group, whereby the R8 group has the meaning according to general formula I. Preferred, optionally substituted, heteroaryl groups are furan, thiophene, pyrrole, pyridine, pyrimidine, quinoline, isoquinoline, phthalazine or quinazoline.
In a preferred embodiment of this invention, at least one compound of general formula I is used, in which groups R1 and R2 together form a (CH2)2-6 chain, which can also be phenyl substituted or attached to a phenyl ring to form a bicyclic system in which the cyclic aliphatic moiety and the phenyl ring share two carbon atoms and groups R3 to R8 and A have the meaning according to general formula I.
Also preferable is the use of at least one compound of general formula I, in which A means an unsubstituted or substituted phenyl, thiophenyl or furyl group and groups R1 to R8 have the meaning according to general formula I.
Also preferable is the use of at least one compound of general formula I, in which groups R5 to R7, the same or different, mean H, a halogen or a CF3 group and groups R1 to R4, R8 and A have the meaning according to general formula I.
Also preferable is the use of at least one compound of general formula I, in which the phenyl ring in general formula I is substituted once or twice in an ortho-position and groups R1 to R8 and A have the meaning according to general formula I.
Also preferable is the use of at least one compound of general formula I, in which A represents a phenyl ring, which is substituted once or twice in an ortho-position and groups R1 to R8 have the meaning according to general formula I.
In a particularly preferred embodiment of this invention, at least one compound of general formula I is used, in which groups R1 and R2 together form a cyclohexyl ring, which can also be phenyl substituted or benzo-condensed, A means an unsubstituted or substituted phenyl, thiophenyl or furyl group and groups R3 to R8 have the meaning according to general formula I.
Also particularly preferable is the use of at least one compound of general formula I, in which A represents a phenyl ring, which is substituted once or twice in an ortho-position and in which the phenyl ring in general formula I is substituted once or twice in an ortho-position and groups R1 to R8 have the meaning according to general formula I.
Quite particularly preferable is the use of at least one of the following compounds of general formula I:
2-(dimethylaminophenylmethyl)-1-phenethylcyclohexanol or the corresponding hydrochloride,
2-[(2-chlorophenyl)dimethylaminomethyl]-1-phenethylcyclohexanol or the corresponding hydrochloride,
2-[(2-bromophenyl)dimethylaminomethyl]-1-phenethylcyclohexanol or the corresponding hydrochloride,
2-[dimethylamino-(3-methoxyphenyl)methyl]-1-phenethylcyclohexanol or the corresponding hydrochloride,
2-(dimethylamino-o-tolylmethyl)-1-phenethylcyclohexanol or the corresponding hydrochloride
2-(dimethylaminophenylmethyl)-1-(3-phenylpropyl)cyclohexanol or the corresponding hydrochloride,
2-(dimethylaminophenylmethyl)-1-[2-(2-fluorophenyl)ethyl]cyclohexanol or the corresponding hydrochloride,
2-[dimethylamino-(2-fluorophenyl)methyl]-1-phenethylcyclohexanol or the corresponding hydrochloride,
2-[(2-chlorophenyl)dimethylaminomethyl]-1-[2-(4-fluorophenyl)ethyl]cyclohexanol or the corresponding hydrochloride,
2-[(2-chlorophenyl)dimethylaminomethyl]-1-[2-(2-fluorophenyl)ethyl]cyclohexanol or the corresponding hydrochloride,
2-[(2-chlorophenyl)dimethylaminomethyl]-1-[2-(3-fluorophenyl)ethyl]cyclohexanol or the corresponding hydrochloride,
1-[2-(2-chlorophenyl)ethyl]-2-(dimethylaminophenylmethyl)cyclohexanol or the corresponding hydrochloride,
1-[2-(3-chlorophenyl)ethyl]-2-(dimethylaminophenylmethyl)cyclohexanol or the corresponding hydrochloride,
1-phenethyl-2-(phenylpiperidine-1-yl-methyl)cyclohexanol or the corresponding hydrochloride,
1-[2-(2-chlorophenyl)ethyl]-2-(dimethylamino-o-tolylmethyl)cyclohexanol or the corresponding hydrochloride,
1-[2-(3-chlorophenyl)ethyl]-2-(dimethylamino-o-tolylmethyl)cyclohexanol or the corresponding hydrochloride,
2-[dimethylamino-(2-fluorophenyl)methyl]-1-[2-(4-fluorophenyl)ethyl]cyclohexanol or the corresponding hydrochloride,
2-(dimethylamino-o-tolylmethyl)1-[2-(4-fluorophenyl)ethyl]cyclohexanol or the corresponding hydrochloride,
1-[2-(2-chlorophenyl)ethyl]-2-(dimethylamino-(2-fluorophenyl)methyl]cyclohexanol or the corresponding hydrochloride,
1-[2-(2-chlorophenyl)ethyl]-2-(dimethylamino-m-tolylmethyl)cyclohexanol or the corresponding hydrochloride,
1-[2-(3-chlorophenyl)ethyl]-2-(dimethylamino-(2-fluorophenyl)methyl]cyclohexanol or the corresponding hydrochloride,
1-[2-(2-chlorophenyl)ethyl]-2-(dimethylamino-(3-fluorophenyl)methyl]cyclohexanol or the corresponding hydrochloride,
1-[2-(2-chlorophenyl)ethyl]-2-(pyrrolidine-1-yl-o-tolylmethyl)cyclohexanol or the corresponding hydrochloride,
1-[2-(2-chlorophenyl)ethyl]-2-(morpholine-4-yl-o-tolylmethyl)cyclohexanol or the corresponding hydrochloride,
1-[2-(2-chlorophenyl)ethyl]-2-(piperidine-1-yl-o-tolylmethyl)cyclohexanol or the corresponding hydrochloride,
1-[2-(3-chlorophenyl)ethyl]-2-(dimethylamino-o-tolylmethyl)cyclohexanol or the corresponding hydrochloride,
2-[dimethylamino-(2-trifluoromethylphenyl)methyl]-1-phenethylcyclohexanol or the corresponding hydrochloride,
2-[dimethylamino-(2-methoxyphenyl)methyl]-1-[2-(2-fluorophenyl)ethyl]cyclohexanol or the corresponding hydrochloride,
2-[dimethylamino-(2-fluorophenyl)methyl]-1-[2-(2-fluorophenyl)ethyl]cyclohexanol or the corresponding hydrochloride,
2-(dimethylamino-o-tolylmethyl)-1-[2-(2-fluorophenyl)ethyl]cyclohexanol or the corresponding hydrochloride,
1-[2-(2-fluorophenyl)ethyl]-2-(pyrrolidine-1-yl-o-tolylmethyl)cyclohexanol or the corresponding hydrochloride,
2-[(2-bromophenyl)dimethylaminomethyl]-1-[2-(2-chlorophenyl)ethyl]cyclohexanol or the corresponding hydrochloride,
2-[(2-chlorophenyl)dimethylaminomethyl]-1-[2-(2-chlorophenyl)ethyl]cyclohexanol or the corresponding hydrochloride,
2-[(2-bromophenyl)dimethylaminomethyl]-1-[2-(2-fluorophenyl)ethyl]cyclohexanol or the corresponding hydrochloride,
2-[(2-chlorophenyl)dimethylaminomethyl]-1-(2-o-tolylethyl)cyclohexanol or the corresponding hydrochloride,
2-[(2-chlorophenyl)dimethylaminomethyl]-1-(3-phenylpropyl)cyclohexanol or the corresponding hydrochloride,
2-(dimethylaminophenylmethyl)-1-(2-o-tolylethyl)cyclohexanol or the corresponding hydrochloride,
2-[(2-bromophenyl)dimethylaminomethyl]-1-(2-o-tolylethyl)cyclohexanol or the corresponding hydrochloride,
2-(dimethylamino-o-tolylmethyl]-1-(2-o-tolylethyl)cyclohexanol or the corresponding hydrochloride,
2-[(2-bromophenyl)dimethylaminomethyl]-1-(3-phenylpropyl)cyclohexanol or the corresponding hydrochloride,
2-[(2-chloro4-fluorophenyl)dimethylaminomethyl]-1-[2-(2-fluorophenyl)ethyl]cyclohexanol or the corresponding hydrochloride,
2-[(2-chloro4-fluorophenyl)dimethylaminomethyl]-1-[2-(2-chlorophenyl)ethyl]cyclohexanol or the corresponding hydrochloride,
2-[dimethylamino-(2-fluorophenyl)methyl]-1-(2-o-tolylethyl)cyclohexanol or the corresponding hydrochloride,
2-[dimethylamino-(2-fluorophenyl)methyl]-1-(3-phenylpropyl)cyclohexanol or the corresponding hydrochloride,
2-(dimethylamino-o-tolylmethyl)-1-(3-phenylpropyl)cyclohexanol or the corresponding hydrochloride,
1-[2-(2-chlorophenyl)ethyl]-2-[dimethylamino-(2-trifluoromethylphenyl)methyl]cyclohexanol or the corresponding hydrochloride,
or
2-[dimethylamino-(2-trifluoromethylphenyl)methyl]-1-[2-(2-fluorophenyl)ethyl]cyclohexanol or the corresponding hydrochloride.
A further object of the invention is also the use of at least one substituted 1-amino-5-phenylpentane-3-ol and/or 1-amino-6-phenylhexane-3-ol compound of general formula I for the manufacture of a medicament for the preventative treatment of cerebrovascular attacks (strokes) and/or the treatment of epilepsy and/or schizophrenia and/or neurodegenerative diseases, in particular Alzheimer""s disease and/or Huntington""s disease and/or Parkinson""s disease and/or cerebral ischaemia and/or cerebral infarction and/or psychoses caused by raised amino acid level and/or cerebral oedema and/or under-supply of the central nervous system, in particular hypoxia and/or anoxia and/or AIDS dementia and/or encephalomyelitis and/or Tourette""s syndrome and/or perinatal asphyxia and/or tinnitus.
The above mentioned medicament may also contain a mixture of enantiomers of at least one compound of general formula I, whereby the enantiomers in this mixture are not present in equimolar quantities. The relative proportion of one of the enantiomers in such a mixture of enantiomers preferably amounts to 5 to 45 percent by mass.
Preparation of the medicament may involve, along with at least one compound of general formula I, further excipients, such as base materials, fillers, solvents, diluents, colorants and binders. The selection of excipients and the amounts to be used depend on whether the medicament is to be administered orally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally or locally. Suitable excipients and their quantities are known to people skilled in the art for each type of administration. For oral administration, medicaments in the form of tablets, lozenges, chewing gums, dragees, capsules, granulates, drops, juices and syrups are suitable, for parenteral, topical and inhalation administration, preferably solutions, suspensions, emulsions, easily reconstituted dry preparations, spheroids, sprays, suppositories or plasters, such as transdermal therapeutic systems, are suitable. For buccal administration, preferably a transmucal therapeutic system is suitable. The compounds of general formula I in depot, in dissolved form or in a plaster, optionally with the addition of a skin penetration medium, are suitable as percutaneous administration forms. Orally or percutaneously applicable preparation forms may release compounds of general formula I with delayed action.
The amount of active ingredient to be given to patients varies according to the patients"" weight, the type of administration, the indication and the severity of the illness. Usually, 0.5 to 50 mg per kg of patients"" body weight of at least one compound of general formula I is administered.
The substituted 1-amino-5-phenylpentane-3-ol and 1-amino-6-phenylhexane-3-ol compounds of general formula I can be manufactured as described below. The R1 to R7 groups and A have the meaning in accordance with general formula I in the following general formulae II to IX.
Through the conversion of Mannich bases of general formula II 
with substituted Grignard compounds of general formula III 
where n=1 or 2 and X=MgCl, MgBr, MgI or Li, in an aliphatic ether, preferably diethylether and/or tetrahydrofuran, a hydrocarbon, preferably hexane or toluene, or mixtures of hydrocarbons and aliphatic ethers, preferably at temperatures between xe2x88x9270xc2x0 C. and +110xc2x0 C., depending on the reaction conditions, preferably tertiary alcohols with the relative configuration of general formula Ia are obtained, 
in which the aminoarylmethyl or aminoheteroaryl methyl group is arranged cis to the hydroxyl group if R1 and R2 form a ring system. With open-chain systems, the analogous relative stereo-chemistry is preferably obtained, which is to be specified as anti. The compounds of general formula I can be obtained free from diastereomers by column chromatographic separation or by crystallisation of the salts thereof, for example hydrochlorides.
In accordance with procedures known from the literature (Houben-Weylxe2x80x94Methods in Organic Chemistry, E21b, 1995, pp 1925-1929), the Mannich bases of general formula II can be obtained by conversion of enamines of general formula IV, 
with an imminium salt of general formula V, 
where Y preferably means Clxe2x88x92, AlCl4xe2x88x92, Brxe2x88x92 or Ixe2x88x92.
The enamines of general formula IV are obtained in accordance with procedures known from the literature through the conversion of ketones of general formula VI 
with secondary amines, preferably dimethylamine, pyrrolidine, piperidine or morpholine. (Acta Chem. Scand. Vol 38, 1984, pp 49-53). The imminium salts of general formula V are manufactured in accordance with procedures known from the literature through the conversion of animals of general formula VII 
with acid chlorides, for example acetyl chloride or thionyl chloride (Houben-Weylxe2x80x94Methods in Organic Chemistry, E21b, 1995, pp 1925-1929).
The imminium salts of general formula V need not be isolated, but instead can be produced in situ and converted, with enamines of general formula IV, to Mannich bases of general formula II (Applied Chem. 106, 1994, pp 2531-2533). Owing to the enamine-imine tautomerism, which is analogous to keto-enol tautomerism, imines of general formula VIII can be used instead of the enamines of general formula IV, 
where R* stands for an alkyl or aryl group. Alternatively, ketones of general formula VI can also be converted directly with imminium salts of general formula V.
However, Mannich bases of general formula II can also be manufactured directly by conversion of enamines of general formula IV with an aromatic or heteroaromatic aldehyde of general formula IX 
and a secondary amine of general formula HNR3R4 (XI), which may also take the form of the corresponding hydrochloride HNR3R4HCl, preferably in the presence of triethylamine, chlorotrimethylsilane and sodium iodide (Synlett 1997, pp 974-976).
The Mannich bases of general formula II are obtained using the above mentioned procedures in relation to the reaction conditions, preferably with the relative configuration of general formula IIa, 
in which the amino group is arranged anti to R1. These compounds of general formula IIa can be obtained free from diastereomers by crystallisation, also of the salts thereof, hydrochlorides for example, or by chromatographic separation.
The representation of Mannich bases of general formula II by 1,4 addition of secondary amines of general formula XI to enones of general formula X, 
which are obtained from the aldol condensation of ketones of general formula VI with aromatic or heteroaromatic aldehydes of general formula IX, is, on the other hand, less stereoselective (U.S. Pat. No. 4,017,637). This procedure is therefore suitable for the representation of other possible stereoisomers.
If chiral amines are used to represent enamines of general formula IV or imines of general formula VIII, then enantiomer-enriched to enantiomer-free Mannich bases of general formula II may be obtained in the subsequent Mannich reaction (Houben-Weylxe2x80x94Methods in Organic Chemistry, E21b, 1995, pp 1925-1929).
1-amino-5-phenylpentane-3-ol and 1-amino-6-phenylhexane-3-ol compounds of general formula I, which contain a phenol, can preferably be manufactured from the corresponding methylether compounds with diiusobutyl aluminium hydride in an aromatic hydrocarbon, preferably toluene, at a temperature between 60xc2x0 C. and 130xc2x0 C. (Synthesis 1975, pp 617-630).
The compounds of general formula I can be converted with the corresponding acids in a known manner into the physiologically tolerable salts thereof. Salt formation preferably takes place in a solvent, for example diethylether, diisopropylether, alkyl acetate, acetone and/or 2-butanone. Furthermore, trimethylchlorosilane in methylethylketone is suitable for the manufacture of hydrochlorides.
Molecular Biological Research
Research to determine the NMDA antagonistic effect of each compound in general formula I was carried out on cerebral membrane homogenates (homogenate of rat brain without cerebellum, pons and medulla oblongata taken from male Wistar rats (Charles River, Sulzfeld, Germany)).
For this purpose, after separating the cerebellum, pons and medulla oblongata, freshly prepared rat brains were macerated in 50 mmol/l of tris/HCl (pH 7.7) with a Polytron homogeniser (model PT3000, Kinematika AG, Littau, Switzerland) at 6000 revolutions per minute (rpm) for 1 minute with ice cooling and centrifuged for 15 minutes at 4xc2x0 C. and 60,000 g. After decanting and discarding the supernatant, again placing in 50 mmol/l of tris/HCl (pH 7.7) and macerating the membrane pellet with a homogeniser at 2000 rpm for 1 minute, it was centrifuged again for 15 minutes at 4xc2x0 C. and 60,000 g. The supernatant was again discarding and the membrane pellet homogenised (2000 rpm for 1 minute) in 50 mmol/l of tris/HCl (pH 7.7) and frozen in aliquots at xe2x88x9270xc2x0 C.
For the receptor bonding test, each aliquot was defrosted and then centrifuged for 15 minutes at 4xc2x0 C. and 60,000 g. After decanting and discarding the supernatant, the membrane pellet was taken up with bonding test buffer and homogenised (2000 rpm for 1 minute). The bonding test buffer was 5 mmol/l tris/HCl (pH 7.7) supplemented with 30 xcexcmol/l of glycine and 100 xcexcmol/l of glutamic acid.
1 nmol/l of (3H)-(+)-MK801 ((5R, 10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptane-5,10-imine was used as a radioactively marked ligand (NET-972, NEN, Cologne Germany). The proportion of unspecific bonding was determined in the presence of 10 xcexcmol/l of non-radioactively marked (+)-MK801 (RBI/Sigma, Deisenhofen, Germany). In further batches, each of the compounds of general formula I were added in series of concentrations and the displacement of the radioactive ligand out of its specific bond to the NMDA receptor determined. All the batches were subjected to triple determinations. The batches were each incubated for 40 minutes at 25xc2x0 C. in a water bath and then harvested for determination of the radioactive ligand bound to the cerebral membrane homogenate by means of filtration through glass-fibre filters (GF/B) (Whatman GF/B, Hassel, Munich, Germany). The radioactivity retained by the glass-fibre filter discs was measured in a xcex2 counter (Packard TRI-CARB Liquid Scintillation Analyser 2000CA, Packard Instrument, Meriden, Conn. 06450, USA) after adding a scintillator (xe2x80x9cReady Proteinxe2x80x9d scintillator, Beckmann Coulter GmhH, Krefeld, Germany).
The percentage inhibition of the specific bonding of the ligand (3H)-(+)-MK801 in the presence of 10 xcexcmol/l of each compound of general formula I resulting from the triple batches is used as a measure of the affinity of the compound for the (+)-MK801 binding site of the ionotropic NMDA receptor. From batches with concentration series of these compounds of general formula I, the IC50 values (concentration of substituted compounds with 50% displacement of radioactive ligand out of its specific bond) were calculated in accordance with the law of mass action using non-linear regression. From these IC50 values, the Kj values were calculated in accordance with the Cheng-Prusoff equation (Y. Cheng, W. H. Prusoff, 1973, Biochem. Pharmacol., 22, pp 3099-3108).
The invention is explained below by means of examples. These examples are used to explain the invention, but they do not restrict the general inventive concept.